We have developed a plan for a NINDS research organization/consortium to develop, characterize and study iPS cell lines for Parkinson's disease (PD). The consortium is organized with several top research teams with both clinical and basic science expertise for PD. The overall goal of this consortium of multiple- Pis (see leadership plan) is to organize the rapidly expanding iPS stem cell field into useful scientific applications and evaluations for clinically oriented PD research. The organizational structure includes a centralized site to generate the iPS cell lines to distribute these to the research teams, and a secure website (www.PDiPS.org). This central facility (Core A) is available at McLean/Harvard and is led by Drs. Isacson, Feng (SUNY) and Jaenisch at MIT. This Core function is also linked with a clinical core (Core B, in close collaboration with Proj 1 - Dr Wszolek) for patient material and analysis, headed by Dr Karen Marder at Columbia University. These types of activities are recorded and coordinated with databases (pd.doc and dbGaP) for known PD mutations and clinical histories, with PD patient fibroblast and blood cell banking made at Coriell cell repository, which also deposits the PD iPS cell lines generated by Core A. With the stem cell iPS cell lines basic characterization fulfilled by Core A and B, these are distributed to the outstanding investigative teams. Project 1: Research team 1 involves both a genetic and genomic analysis team, which also provides insight into new mutations, both at the familial and genetic association level as risk factors. This team is led by Zbigniew Wszolek as a clinical director and Matt Farrer for genetic studies (as Pis). Their recent analysis and genetic technology will benefit the continued work. In Project 2 there is a molecular characterization of the various cell lines. This team is headed by Dr. Ted Dawson, who will be working with his collaborators to have iPS line analyses from relevant PD patient material. Dr. Dawson also has a current collaboration through Project 1 with Dr. Wszolek, and they are already moving towards setting up these cell lines for molecular characterization. In Project 3 a U. Penn research team led by Drs. Lee and Trojanowski will carry out investigation into PD protein processing, degradation and autophagy analysis of PD patients'iPS cells. Their outstanding expertise in this field will allow a state of the art analysis of changes relevant to such cell biological processes. Project 4 will be an essential in vitro physiological and toxicological analysis, and critical in vivo bioassays for long-term evaluation of PD iPS cell derived DA neurons. This project team is headed by Drs. Isacson and Surmeier, who by collaboration will perform both in vitro and in vivo assays for any altered electrophysiologic and neurotoxic response of the PD iPS derived cells;providing neurobiology of disease information for neuronal/neuritic growth, vulnerability and calcium buffering capacities. Finally, Project 5, headed by Dr Serge Przedborski, will examine the highly relevant PD molecular mechanisms and pathology of mitochondria in differentiated PD iPS neurons. Overall, this PD iPS consortium will have an exceptional research capacity, which is currently ready to deploy by the independent strengths and expertise of the individual research teams. The GO grant will enable a consortium that quickly can provide a national resource for iPS cell lines relevant to PD, to be characterized in a meaningful way by the assembled collaborators, and made available as useful reagents to the large community of present and future PD researchers. PUBLIC HEALTH RELEVANCE: We use stem cells generated from Parkinson's disease patients'skin to produce a specific population of purified neurons that retain the authentic genetic risks for the disease. We will determine if these neurons are more susceptible to Parkinson's disease-like degeneration than neurons generated from healthy people's skin. Our data will aim to establish these neurons as a powerful new approach to understanding the complex disease process and a future tool for drug discovery.